Hematopoietic stem cell–engrafted NOD/SCID/IL2Rγnull mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses

Watanabe, Sumio; Terashima, Kazuo; Ohta, Shinrai; Horibata, Shigeo; Yajima, Misako; Shiozawa, Yoko; Dewan, M. Zahidunnabi; Yu, Zhong; Ito, Mamoru; Morio, Tomohiro; Shimizu, Norio; Honda, Mitsuo; Yamamoto, Naoki

doi:10.1182/blood-2006-04-017681

Cited by 188 publications

(186 citation statements)

References 39 publications

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“…In a recent report, NOD/SCID/ IL2R␥-null mice humanized by cord blood-derived CD34 ϩ cells have been shown to support HIV-1 infection with both CCR5-and CXCR4-tropic HIV-1 isolates for more than 40 days. 25 Anti-HIV-1 antibodies are detected only in animals with high levels of viral infection. The DKO-hu HSC mouse, and its improved derivatives, will facilitate development of novel therapeutic strategies for controlling HIV-1 diseases.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 infection and pathogenesis in a novel humanized mouse model

Zhang

Kovalev

2006

Blood

127

136

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IntroductionThe hallmarks of AIDS are high levels of HIV-1 infection, depletion of CD4 ϩ T cells, and loss of immunity. The mechanism of HIV-1 immunopathogenesis is not clear because human patients are the only hosts that support high levels of HIV-1 replication and develop AIDS. Extensive studies have been performed in primate models with either low levels of HIV-1 replication (HIV-1 in chimps) or a different virus (simian immunodeficiency virus [SIV] or simian/human immunodeficiency virus [SHIV] in monkeys). 1-3 HIV-1 fails to infect murine cells due to blocks at multiple steps of the HIV life cycle. The mouse with a reconstituted human immune system would be an ideal small animal model for studying HIV-1 infection and pathogenesis. A number of human-mouse chimeric models have been developed, but with only limited success. The severe combined immunodeficient (SCID)-hu Thy/Liv mouse has an intact human thymus organ, thus allowing investigation of HIV-1 pathogenesis in a human lymphoid organ. [4][5][6] However, very low levels of human T cells are detected in the peripheral lymphoid organs or blood. The hu-peripheral blood lymphocyte (PBL)-SCID mouse supports transient and selective engraftment of xenoreactive human T cells. 7,8 Human CD34 ϩ cells transplanted into SCID or nonobese diabetic (NOD)/SCID mice lead to generation of mainly human myeloid and B cells in the mouse bone marrow, but inefficient generation of human T cells. 9,10 When CD34 ϩ human hematopoietic stem cells (HSCs)/hematopoietic stem progenitor cells (HSPCs) are injected directly into the liver of newborn Rag2-␥C double-knockout (DKO) mice, which lack T, B, and natural killer (NK) cells, the newborn liver environment of DKO mice supports efficient engraftment and development of a functional human immune system in central and peripheral lymphoid organs. 11,12 To demonstrate that the DKO-hu HSC mouse can support efficient HIV-1 infection with relevant immunopathogenesis, we show that CCR5 and CXCR4, the HIV-1 coreceptors, are both expressed on human T cells in central and peripheral lymphoid organs. DKO-hu HSC mice allow high plasma viremia with high levels of HIV-1 infection in lymphoid organs. Both CD4 ϩ CD45RO ϩ and CD4 ϩ CD45RO Ϫ T cells are productively infected in lymphoid organs. Human CD4 ϩ T cells are gradually depleted by HIV-1 in a dose-dependent manner. In addition, HIV-1 infection persists in infected DKO-hu HSC mice for at least 19 weeks, with recoverable infectious HIV-1 in lymphoid tissues. Materials and methods Construction of DKO-hu HSC mice with human CD34 ؉/؊ cells from cord blood or fetal liverHuman CD34 ϩ cells were isolated from cord blood (CB) or fetal liver (FL) tissues. FL CD34 ϩ (1 ϫ 10 6 ) or CB CD34 ϩ (1 ϫ 10 5 ) cells were injected intrahepatically into each newborn DKO mouse previously irradiated at 400 rad. 11 Human leukocytes (CD45 ϩ ) were analyzed for CD3, CD4, CD8, CD45RO, CD19, CCR5(2D7), and CXCR4(12G5) by fluorescenceactivated cell sorting (FACS). 13 HIV-1 infection and pathogenesis in DKO-hu HSC miceAt l...

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Section: Resultsmentioning

confidence: 99%

HIV-1 infection and pathogenesis in a novel humanized mouse model

Zhang

Kovalev

2006

Blood

127

136

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“…Although all groups were able to show infection of HIV (both CCR5-and CXCR4-tropic virus) in peripheral blood, long term viremia, and depletion of CD4 + T-cell populations similar to HIV-infected patients, they were unable to demonstrate appreciable levels of anti-HIV antibody responses. Interestingly, Watanable et al was able to demonstrate in the NOD/Shiscid IL2Rγ −/− mouse sustained viremia and humoral immune response specific to HIV envelope and gag proteins [124]. In an attempt to evaluate the humanized mouse model as an appropriate model for HIV transmission studies, two independent groups were able to demonstrate transmission of HIV via mucosal routes of infection.…”

Section: Emerging Humanized Mouse Models For the Study Of Hiv Infectimentioning

confidence: 97%

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

et al. 2008

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FoxP3 + CD4 + CD25 + regulatory T (Treg) cells are implicated in a number of pathologic processes including elevated levels in cancers and infectious diseases, and reduced levels in autoimmune diseases. Treg cells are activated to modulate immune responses to avoid over-reactive immunity. However, conflicting findings are reported regarding relative levels of Treg cells during HIV-1 infection and disease progression. The role of Treg cells in HIV-1 diseases (aberrant immune activation) is poorly understood due to lack of a robust model. We summarize here the regulation and function of Foxp3 in Treg cells and in modulating HIV-1 replication. Based on recent findings from SIV/monkey and HIV/humanized mouse models, a model of the dual role of Treg cells in HIV-1 infection and immuno-pathogenesis is discussed. KeywordsRegulatory T cells; AIDS; Chromatin; Epigenetic; Humanized mouse; DKO-hu; ONTAK Regulatory T cells play an important role in self immune tolerance and in balanced immune responsesThe regulation of immune tolerance is a critical aspect of immunology. The balance between recognition of self versus non-self is essential for maintenance of immune homeostasis. Regulatory T cells (CD4 + CD25 + ) are a crucial component for the control of deleterious effects from excessive immune responses as seen in autoimmune disease or allergic insult [1,2]. Treg cells have been implicated in a number of pathologic processes including elevated levels in cancers [3][4][5] and infectious diseases [6][7][8][9], and reduced levels in autoimmune diseases [1,[10][11][12][13]. It is apparent that Treg cells are induced (or recruited and expanded) by most infections to modulate host immune responses to avoid overreactive immunity (Fig. 1). As a result, Treg play a critical role in immune responses, vaccinations as well as in immunopathogenesis of pathogens. For example, Leishmania infection leads to induction of Treg that help to maintain the balance of immune response and pathogen persistence [18,19]. For the host, persistence of the pathogen is beneficial to maintain effective immunity against these pathogens [18]. In a number of chronic viral infections, Treg are induced to subdue the anti-viral immune responses and allow persistent infection. Mechanisms of CD4 T-cell differentiationT-cell lineage commitment and activation of T cells are usually accompanied by changes in patterns of gene expression. During T-cell responses, T helper (Th) progenitor cells will undergo Th1 or Th2 lineage commitments involving well-defined initiation cytokines, transcription factors, and effector cytokines. Expression of T-bet and GATA3 in Th1 and Th2 cells, respectively, is epigenetically regulated by histone modification and DNA methylation. As T lineage determinants, T-bet or GATA3 are also involved in epigenetically reprogramming the T-cell genome to silence the Th2 or Th1 effector cytokines, respectively, and to activate Th1 or Th2 cytokine genes for transcription (Fig. 2). Similarly, Th17 cell differentiation requires IL-6/TGF-β (mo...

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“…17 By injecting hCD34 þ cells in NSG mice, we observed a human immune reconstitution very similar to what is observed by others using the same mouse model. [73][74][75][76][77] This model does not mimic exactly what is usually observed after HSCT in a clinical setting, but is nevertheless considered the best animal model to study in vivo immune reconstitution induced by hCD34 þ cells. As for GvHD, this model also allows the study of a given treatment used alone.…”

Section: Discussionmentioning

confidence: 99%

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

Gregoire-Gauthier

Durrieu

Duval

et al. 2011

Bone Marrow Transplant

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The efficacy of IVIG in preventing GvHD has not been definitely demonstrated clinically. Using a xenogeneic model of GvHD in NOD/SCID/ccÀ (NSG) mice, we showed that weekly administration of IVIG significantly reduced the incidence and associated mortality of GvHD to a degree similar to CsA. Unlike CsA and OKT3, IVIG were not associated with inhibition of human T-cell proliferation in mice. Instead, IVIG significantly inhibited the secretion of human IL-17, IL-2, IFN-c and IL-15 suggesting that IVIG prevented GvHD by immunomodulation. Furthermore, the pattern of modification of the human cytokine storm differed from that observed with CsA and OKT3. Finally, in a humanized mouse model of immune reconstitution, in which NSG mice were engrafted with human CD34 þ stem cells, IVIG transiently inhibited B-cell reconstitution, whereas peripheral T-cell reconstitution and thymopoiesis were unaffected. Together these in vivo data raise debate related to the appropriateness of IVIG in GvHD prophylaxis. In addition, this model provides an opportunity to further elucidate the precise mechanism(s) by which IVIG inhibit GvHD.

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Hematopoietic stem cell–engrafted NOD/SCID/IL2Rγnull mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses

Cited by 188 publications

References 39 publications

HIV-1 infection and pathogenesis in a novel humanized mouse model

HIV-1 infection and pathogenesis in a novel humanized mouse model

Foxp3 and Treg cells in HIV-1 infection and immuno-pathogenesis

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

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